In 1968, the 25-hydroxy-vitamin D3 (25-(OH)D3) molecule was discovered as the major blood form of vitamin D circulating in the body. (Blunt J W et al., 1968, 25-Hydroxycholecalciferol: A biologically active metabolite of vitamin D3, Biochemistry 7:3317-3322).
25-(OH)D3 was first patented in 1971 by DeLuca et al. (U.S. Pat. No. 3,607,888). Over the course of many years, measurement of 25-(OH)D3 blood levels has been a significant commercial enterprise.
A large amount of work suggests that 25-(OH)D3 blood levels are an excellent measurement of the vitamin D status of a patient who might be suffering from a metabolic bone disease. (Jones G et al., 1998, Current understanding of the molecular actions of vitamin D, Physiol. Rev. 78:1193-1231).
Recently, a large number of epidemiological studies correlate 25-(OH)D3 blood levels to a reduced risk of a number of conditions: colorectal cancer (Gorham E D et al., 2007, Optimal vitamin D status for colorectal cancer prevention—A quantitative meta analysis, Am. J. Prev. Med. 32(3):210-216); breast cancer (Garland C F et al., 2007, Vitamin D and prevention of breast cancer: Pooled analysis, J. Steroid Biochem. and Mol. Biol. 103:3-5 Special issue, pp. 708-711); prostate cancer (Li H J et al., 2007, A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer, Plos Medicine 4(3):562-571); and, autoimmune diseases such as multiple sclerosis and type 1 diabetes (Munger K L et al., 2007, Elevated serum 25-hydroxyvitamin D predicts a decreased risk of MS, Multiple Sclerosis 13(2):290; and, Hyppönen, E Läärä et al., 2001, Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study, Lancet 358:1500-1503). Thus, 25-(OH)D3 plasma levels have become a focal point of public health policy in the United States and many other countries.
25-(OH)D3 is no longer available in the U.S. market. It is not available as a prescription drug nor as a vitamin supplement. However, 25-(OH)D3 plasma levels are measured to assess vitamin D status.
At a 25-(OH)D3 blood level concentration greater than 450 ng/ml, toxicity becomes a concern. (Shepard R M et al., 1980, Plasma Concentration of Vitamin D3 and Its Metabolites in the Rat as Influenced by Vitamin D3 or 25-Hydroxyvitamin D3 Intakes, Arch. Biochem. Biophys. 202:43-53).
To promote public health, vitamin D production and administration have focused on exposure to ultraviolet light. (Sayre R M et al., 2007, Reintroduction of a classic vitamin D ultraviolet source, J. Steroid Biochem. and Molecular Biol. 103(3-5 Special Issue):686-688; and, Rajakumar K et al., 2007, Solar ultraviolet radiation and vitamin D: A historical perspective, Am. J. Public Health 97(10):1746-1754).
Dermatologists are not in favor of using skin production of vitamin D to meet increased blood level concentrations. Small amounts of ultraviolet light exposure markedly increases the risk of melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin. (Lim H W et al., 2007, Commentary: A responsible approach to maintaining adequate serum vitamin D levels, J. Am. Acad. Dermatology 57(4):594-595).
Currently, the only forms of vitamin D available in the U.S. are vitamin D3 and vitamin D2, which are present in cod liver oil. However, cod liver oil contains significant amounts of other biopotent materials such as vitamin A. (Griffing G T et al., 2008, Mother was right about cod liver oil, Medscape J. Med. 10(1):8).
It has been reported that the conversion of vitamin D3 to 25-(OH)D3 in vivo is not quantitative. (Heaney R P et al., 2008, 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions, Am. J. Clin. Nutr. 87(6):1738-1744).
Upon administration of vitamin D3 or vitamin D2, often, a significant amount of it is deposited in lipid depots, and, vitamins D3 and D2 remain there until the lipid is mobilized. (Mauer E B et al., 1972, Distribution and storage of vitamin-D and its metabolites in human tissues. Clin. Sci. 43(3):413-431 (1972); Rosenstreich et al., 1971, Deposition in and release of vitamin D3 from body fat: Evidence for a storage site in the rat, J. Clin. Invest. 50(3):679-687).
Continued vitamin D3 supplementation intake causes increased concentrations levels in the adipose tissue, which eventually reaches saturation and forces elevated conversion to 25-(OH)D3. Such conversion, however, causes vitamin D intoxication, which is difficult to resolve.
Deficiency or insufficiency of vitamin D exists in the human population, which has been extensively reported in the clinical literature. (Looker A C et al., 2002, Serum 25-hydroxyvitamin D status of adolescent and adults in two seasonal subpopulations from NHANES III, Bone 30(5):771-777).
An increased incidence of childhood rickets and osteomalacia has been reported to exist in the inner cities and in dark skinned immigrants living in the Northern hemispheres. (Thacher T D et al., 2006, Nutritional rickets around the world: causes and future directions, Annals of Tropical Paediatrics 26(1):1-16).
Some commentators have theorized that vitamin D insufficiency contributes to the bone erosion process, i.e., osteoporosis. (Looker A C et al., 2008, Serum 25-hydroxyvitamin D and hip fracture risk in older U.S. white adults, J. Bone Min. Res. 23(1):143-150).
In patients suffering from chronic kidney disease, there is evidence of vitamin D insufficiency that may contribute to continued disease progression (Chonchol M et al., 2007, 25-Hydroxyvitamin D, insulin resistance, and kidney function in the Third National Health and Nutrition Examination Survey, Kidney Int. 71(2):134-139). Hence, there exists a long-felt and important unmet need for maintaining higher blood levels of 25-(OH)D3.